Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems."

It is a truism that as we age there are a number of underlying physiological changes conspiring to alter our level of behavioral and cognitive function ing. Despite the inherent interrelatedness of these behavioral and cognitive changes, all too often the papers we read confine themselves to specific, isolated components of the developing process. Although exceptions nat urally exist, we believe that these exceptions should become rule. Although an integrated approach is important in all areas of adult devel opment, it is perhaps particularly germane in the study of atypical aging. Here, changes in overall functioning can occur in rapid succession, with the synchrony of decline between different subprocesses making it difficult to factor changes in one process from changes in another. For example, because changes in cognitive functioning co-occur with other dramatic changes in (motoric) response capacities, it is unclear how one can effec tively study changes in the ability to cognize independent of changes in the very mechanisms (ability to execute motor sequences) so often used to index cognitive performance."

The physiology and metabolism of thyroid hormones were areas of intense research investigation during the 1970s. Radioimmunoassays were applied to study the concentration of iodothyronines in biologic fluids. These techniques proved to be highly sensitive, specific, and reproducible as well as rapid. The availability of specific radioimmunoassays led to the detection of several iodothyronines in human biologic fluids, e. g., reverse triiodothyronine (rT 3), diiodothyronines, monoiodothyronines, and acetic acid derivatives of thyroxine (T 4) and T 3, which were previously either unknown or briefly considered but forgotten in the 1950s. This monograph is intended for readers who desire an overview of thyroid hormone physiology as it was understood in 1979. It should be especially useful to trainees in endocrinology and individuals interested in potential research projects. The main focus has been on the studies conducted between 1969 and 1978, alt lOugh other information has been reviewed to provide an overall working knowledge of the field. A list of over 500 references, although probably still incomplete, should lead a reader to at least a few important articles in each area relevant to thyroid hormone physiology.

As far as we are aware, this is the first attempt to cover the com parative physiology of the pancreatic islets in a monograph. The topics discussed would probably have sufficed to fill about half a dozen monographs, a matter that becomes obvious from a look at the Contents. Hence, we have tried to present the ma terial more in the form of a digest, to emphasize evolutionary perspectives, to point out critical issues, and to identify challenging topics for future research. This approach required an arbitrary reduction of the num ber of references, and we therefore join the chorus of recent authors who beg their colleagues for understanding if some of their publications do not appear in the bibliography. Keeping up with the current literature was like fighting one of those monsters that grow a couple of new heads for each one that is cut off. Nevertheless, we hope that we have covered most of the key publications up to the autumn of 1986. We gratefully acknowledge the advice of many colleagues, and in particular the invaluable criticisms of Robert L. Hazelwood and Erika Plisetskaya. Special thanks are due to the series editor, Donald S. Farner, for his patience and guidance, both of which were fresh proof of his legendary diplomatic skills. Finally, we wish to thank Dr. D. Czeschlik and his staff at the Springer Verlag for their patience and support. Philadelphia, PA AUGUST EpPLE Greenville, NC JACK E. BRINN September 1987 v Contents Chapter 1. Introduction .......................... ."

The tridecapeptide neurotensin (NT) was first identified in bovine hypothalamic extracts and characterized by Carraway and Leeman (1973,1975,1976) and has subsequently been found in all classes of vertebrates (Carraway and Leeman 1976; Kitabgi et al. 1976; Kataoka et al. 1979; Langer et al. 1979; Reinecke et al. 1980a; Cooper et al. 1981; Grant et al. 1982; Carraway et al. 1982; Eldred and Karten 1983), many invertebrates (Reinecke et al. 1980 b; Grimmelikhuijzen et al. 1981; Price et al. 1982), and certain bacteria (Bhatnagar and Carraway 1981). It is distributed throughout the mammalian central nervous system (CNS) (Uhl and Snyder 1977 a, b), gastrointestinal tract (Sundler et al. 1977; Schultzberg et al. 1980), cerebrospinal fluid (CSF), adrenals, pancreas, and plasma (Fernstrom et al. 1980). When administered systemically, the peptide has a variety of effects such as hypotension, hyperglycemia, decreased gastric acid secretion, decreased gut motility, and altered secretion of anterior pituitary hormones (Leeman and Carraway 1982). NT apparently does not cross the blood-brain barrier in appre- ciable quantities; however, when administered directly into the CNS, it produces a number of physiological and behavioral effects. A burgeoning body of evidence supports the role of NT as a neurotransmitter or neuromodulator. Thus far, het- erogeneous CNS distribution, release of NT upon neuronal depolarization, satu- rable and specific binding of NT to receptors, and degradation by peptidases have all been demonstrated.

The term polycystic ovary syndrome (peOS) is meant to describe a clinical endocrinopathy characterized by menstrual irregularity and evidence of hyperandrogenism. While recognized since the 1800s, a clinical composite was not constructed until 1935 when Stein and Leventhal reported their findings of seven women with infertility, menstrual dysfunction, hirsutism, and enlarged ovaries. Notably, the ovaries contained numerous multiple cysts and the ovarian capsule was thickened. At the time, this preciseness of definition was sufficient to entitle the entity Stein-Leventhal syndrome. Subsequently, over the intervening years as investigators attempted to un ravel the pathophysiology and genesis of this disorder and the number of reported studies increased, there ensued a gradual and distinct terminologic conversion to polycystic ovary syndrome, which, whether intentional or not, connoted a less well-defined condition. Perhaps this is appropriately so, given the seemingly broadening spectrum of clinical presentations and the continuing debate over what constitutes peos. The expansive new knowledge about peos was discussed to a significant degree at an international symposium organized by Serono Symposia USA and held in Boston in the late spring of 1995. Ovarian physiology, including the fate of the follicular unit, was a central focus with several presentations on the genesis, growth, and death of ovarian cellular components. A discus sion of the regulation of ovarian cell function was also highlighted and comprised a major portion of the program."

The epididymis has great significance in the reproductive biology of the male and it is gaining recognition as an organ worthy of study in its own right - where the secretory and absorptive activities of one tissue (the epithelium) profoundly modify the function of another (the spermatozoon). Apart from cases of epididymal agenesis or physical blockage, however, it is not yet known to what extent mal functions of the epididymis contribute to "unexplained" male infer tility, but its importance as a target for antifertility agents in the male is now widely appreciated. This monograph evolved from two lectures on epididymal func tion given at the National Research Institute for Family Planning, Beijing and the Sichuan Provincial Family Planning Research Insti tute, Chengdu, China in 1983. In order to stress for this audience the central importance of the epididymis in fertilisation, and so highlight its potential for attack by antifertility agents, the talks attempted to put the epididymis in reproductive perspective by stressing the func tional development of the sperm cells during their sojourn in the epididymis, rather than merely listing the changes observed in them."

Contraceptives have always provided ground for controversy. This book describes and discusses latest findings concerning the advantages as well as hazard and risk factors of contraception. The clinical impact of oral contraceptives on metabolism is particularly highlighted. In addition, behavioral methods, intrauterine devices, implants and modern approaches in animal and clinical research in the field of immunization against pregnancy are considered. Last, but not least, the book summarizes the complex ethical, religious and political aspects of family planning and contraception.

This monograph brings together our work concerning the relationships be tween the hypothalamus, pituitary and testis. The studies span approximate ly a decade of collaborative work. Over this period our contributions and those of many others have advanced greatly our understanding of many aspects of male reproductive biology. This monograph attempts to survey these developments and to highlight many unresolved issues. It also provides an opportunity to demonstrate the value of investigations which relate bio chemical to structural parameters and to illustrate the importance of animal studies in elucidating biological principles with clinical applications. The reverse is also important since the pathophysiology of human disorders of ten provides insight into hitherto unsuspected basic mechanisms. In any rapidly expanding field it is difficult to stop revising and extending a manuscript. It is equally difficult to quote every reference in the field but we trust that those of significance have not been omitted. Some of our former students have collaborated with us as co-authors in producing this monograph. It is equally important to recognise the contributions of our other former students and colleagues who have physically participated in the studies and without whose intellectual contributions a number of concepts would not have been elucidated. Their work is acknowledged in the text of the monograph and the extensive list of references."

The authors of this book have a goal-to describe the management of infertility from the perspective of physiology and anatomy gone awry. To accomplish this goal, the chapters devoted to the causes of infertil ity begin with a description of the normal structure and function of the organ or system causing the infertility. We believe that under standing the normal will result in rational and effective diagnosis and treatment of infertility. Our intent is that this book be a useful re source for those who care for infertile couples. For an infertile couple, success is the delivery of a normal and healthy infant. Chapters that describe the causes and treatment of habitual abortion and the reproductive performance of previously infertile couples emphasize the hazards that exist between conception and birth. Our environment is one of these hazards, one that may also affect reproduction before conception. A chapter is devoted to a de scription of environmental agents that affect reproduction, the mech anisms of their effect, and methods to predict those present and future environmental agents which might also affect reproduction."

It is about 15 years since the first presentation on uteroglobin was given to a group of developmental biologists, reproductive physiologists, and geneticists who had gathered in November 1966 at Konstanz (Germany). In the following decade so much knowledge was accumulated that a special symposium seemed appropriate. This was organized as a satellite symposium to the International Congress of Endocrinology at Hamburg and brought together 50 scientists at Aachen. These scientists, working in the field of pro teins and steroids, in early pregnancy, recognized the impact of what had been reported, and many of them later agreed to contribute to this booN. and thus to present their research d, ta available until December 1980. The present volume covers a relatively broad spectrum of data and observations which shed some light on preimplantational embryonic life and on the supports and obstacles provided by the maternal organism with respect to final accomplishment of normal im plantation and establishment of pregnancy. The book will serve both as a textbook and as a scientific dictionary for Ph.D. students, postdoctoral fellows and advanced scientists working in this area. The course of early pregnancy depends very much on a proper balance of steroid hor mones, and the induction of protein synthesis by steroid hormones is one of the well known fundamental processes in cellular differentiation and embryonic development."

Early embryonic loss is a continuing social and economic global problem. In human populations the estimates of interruptions early in pregnancy range from 35-60%. In animal husbandry (swine, ruminants) fully 30% of pregnancies fail to survive early events of gestation. The futility associated with this persistant high risk is even more unsettling because of advances made in assisted reproductive technology which, although this very selective methodology has added to our knowledge of embryo-endometrial interactions, has resulted in a birth rate of only 14%. These studies have instigated comparisons of the live relative contributions of the embryo and the uterus to the outcome of pregnancy. These analyses have shown that we have learned significantly less about the role of the uterus in deciding the outcome of either natural or assisted pregnancies. In 1979 a quotation by George Corner was used to set the tone of a meeting that was devoted to discussion of the cellular and molecular aspects of implantation. In spite of the proliferation in research activity which occurred in the following 15 years our real understanding of the embryo transfer process has fallen short of our expectations. We use the Corner quotation, once again, to preface this symposium so that we may recall that the fundamental nature of the process which regulates embryo-endometrial interactions still escapes us.

The role of electrical signalling in the control of endocrine secretions by the brain has been clear for many years. Recently, the influences of hormones on synthetic events in neuroendocrine cells have raised new questions concerning the peptides released from such neurons. This volume concentrates on the relation between these two fields and asks how electrical action potentials facilitate secretion of substances from nerve cells which control endocrine events. While stimulus-secretion coupling has been studied extensively in other physiological contexts, this is the first treatment of the phenomenon in an exclusively neuroendocrine setting.

The Organon Symposia have actually become a tradition, keeping up with exciting developments in reproductive medicine. The purpose of this symposium on "Fertiliza tion of the Human Egg in Vitro" was to bring together the stilllimited number of elinical specialists in the field and to stimulate another group of basic research people to exchange their experiences and knowledge, hopefully promoting elose cooperation between the two groups. It was a kind of scientific "first" that all research teams so far successful in achieving the birth of a healthy baby, fertilized in vitro came together at a workshop conference without a large audience of spectators and reporters, but with a small number of highly critical colleagues from the fields of basic reproductive physiology and comparative developmental biology. This atmosphere allowed for the elose exchange of results, hypotheses, diagnostic and therapeutic procedures, criticism, and respect, and created very productive discussions, all of which furthered the aim of the method: To help more childless couples to have their own babies by the ultima ratio procedure of in vitro fertilization and embryo replacement. The book that has emerged from this symposium will help to disseminate the great amount of information and experience gathered among the scientifically and clinically interested colleagues of many other hospitals and universities who could not be invited to the meeting. At the same time, it will prove that there is much more work to be done in the basic and clinical sciences of human embryology and reproductive biology."

The various congresses on growth hormone (GH) which have been held in Milan since 1967, the Milan Congresses, have witnessed over 25 years the tremendous expansion of a research field that was based initially upon the scarce knowledge of the biological properties of a protein. GH, whose chemical structure had just been identified and a radioimmunoassay developed for its measurement in blood, became in the following years a major area of biological research. The boundaries have since become blurred, as the research area has extended to the physiology and pathology of growth, puberty and reproduction, and the control of metabolism during the whole lifespan. Since the last GH Congress held in 1987, GH studies using the molecular biological approach have resulted in the puri fication, cloning and expression of the human GH (hGH) recep tor and binding protein, in new and exciting information on the insulin-like growth factors (IGF) and their paracrine and autocrine roles, and in the awareness that a panoply of binding proteins are present in the extracellular fluids and can, possibly, modulate IGF-receptor interactions and, thus, IGF actions. Finally, the availability of large amounts of biosynthetic hGH, besides allow ing more extensive clinical use in states of GH deficiency and extrasomatotrophic pathologies, has permitted disclosure of im portant metabolic effects of hGH during adulthood and, perhaps, aging and in many protein catabolic states."

Sixteen years is a long time, not only in human life but also in the rapid history of contemporary endocrinology. Since the publication of the first edition of this monograph, numerous new lines of research and discoveries have greatly contrib- uted to our knowledge of the physiological and pathological regulation of aldos- terone biosynthesis in man and animals. The first reports about a sensitive ra- dioimmunoassay for plasma aldosterone and about a preparation of dispersed zona glomerulosa cells were published in 1970 (Mayes et al. 1970; Haning et al. 1970). These two developments alone turned out to have a tremendous impact on research in aldosterone physiology (for reviews see Coghlan et al. 1979b; J. F. Tait et al. 1980b). In 1971, atrial natriuretic peptides, somatostatin, and the precursor molecule of ACTH had not yet been discovered. Angiotensin antagonists and con- verting-enzyme inhibitors were not yet available. The clinical syndrome of hypo- reninemic hypo aldosteronism was unknown. The possible roles of prostaglandins and dopamine in the control of aldosterone pwduction had not been considered. Cyclic AMP was then the only substance with a clearly established second-mes- senger function.

From the discovery of Pdx1, the first "master gene" of pancreatic development, to the most recent findings on the role of microRNAs in beta cell homeostasis, the last fifteen years have seen an unprecedented advance in our understanding of the precise development and organization of the many different cell types that make up the pancreas. It is now widely acknowledged that the therapeutic differentiation of stem cells into pancreatic cells is an ambitious endeavor that will not succeed without a thorough understanding of the molecular processes underlying the native development of the organ. This book, aimed at experts and students alike, offers a comprehensive review of the state of the art in both pancreatic development and regeneration. The many strategies to differentiate adult and embryonic stem cells into pancreatic beta cells are also discussed in the context of potential therapeutic interventions for type I diabetes.

Diabetes is now reaching epidemic proportions, and the associated complications of this disease can be disabling and even life-threatening. In Type 2 Diabetes: Methods and Protocols, leading investigators provide up-to-date explanations of commonly used laboratory protocols used in diabetes research. Covering the commonly described in vivo and in vitro model systems, the volume ultimately leads to an overall view of how cellular dysfunction and degeneration leads to susceptibility and diabetes disease progression. Written in the highly successful Methods in Molecular Biology series format, chapters include brief introductions to their respective subjects, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and expert notes on troubleshooting and avoiding known pitfalls.

Comprehensive and cutting-edge, Type 2 Diabetes: Methods and Protocols offers succinct, proven techniques to aid research scientists and clinicians in continuing the study of this debilitating disease."

A Guide to the Practice of Paediatric Endocrinology concisely catalogs and analyzes the hormonal problems of children and offers practical guidance for their diagnosis and treatment. The author examines each of the endocrine glands and covers such topics as sexual development, growth, weight, puberty, thyroid disorders, adrenal disorders, salt and water balance, calcium balance, glucose homeostasis, and neoplasia. He then suggests practical procedures for managing ailments in each of these areas, including tests, imaging, and drug treatment, with specific information on normal values for the tests and guides to drug dosages. The volume is illustrated throughout with photographs and clear, informative charts. For all pediatricians and endocrinologists, this book will be a vital resource on hormonal disorders in children.

A variety of new techniques that promise to revolutionize the clinical management of early pregnancy are fully detailed in this state-of-the-art book. Leading international researchers describe fast-moving topics such as embryo manipulation and the diagnosis of congenital abnormalities. The technology of assisted reproduction has made it possible to study living embryonic material for the first time, which has led to rapid advances in our understanding of the human embryo's early development. For example, study of the embryo in the test tube has pointed to early pregnancy loss as a possible cause of later infertility. Even more important, diagnostic tests using sophisticated techniques of molecular biology can be run on single cells before the embryo is replaced in the uterus. Another area of advance is the diagnosis of congenital abnormalities in the first and second trimesters of pregnancy. Great improvements have been made in the techniques of chorion villus biopsy and ultrasound imaging. A spectrum of simple biochemical tests performed on the mother's blood can greatly improve the detection of Down syndrome and other chromosome defects. Together with other developments in the fields of molecular biology and endocrinology, these new diagnostic techniques are the beginning of a new age in clinical human genetics and embryology.

In vitro fertilization has resulted in an estimated 4000-5000 births in the world. The procedure has been accepted in Europe, America and Australia and several hundred IVF clinics are operating successfully. The newer procedures of GIFf, embryo freezing and donor oocyte IVF have become established and are dealt with in several chapters. GIFf has become the procedure of choice for patients with infertility of unknown origin. Oocyte freezing represents an important new technology which is being developed. The routine IVF procedure has improved slightly; variation in results can be reduced by quality control of laboratory and clinical techniques. Male factor infertility has been dealt with by IVF in mild and moderate cases, but newer techniques will be required to deal with severe problems in the male. Most countries have accepted that the straightforward IVF pro cedure is ethical. Limitations concerning the use of donor oocytes and embryo experimentation exist in some religions and countries; legal control of the new reproductive technologies ranges from the passage of statutes to no control at all. Many countries are still considering the need for legislative control. The text endeavours to indicate new areas of importance and to guide those organizing services as to how to introduce newer technolo gies.

Publication of this monograph acknowledges great strides made in research on the zona pellucida during the past decade or so. The body of work presented testifies to a resurgence of interest in the zona pellucida, prompted largely by a renewed appreciation of its unique properties and its important functions during early mam malian development. It is gratifying to realize that the zona pellucida has at last achieved a well-deserved attention. Whereas extracellular coats of nonmammalian eggs have been studied intensively for many years, the zona pellucida by comparison, has until now taken a back seat. Fortunately, the research presented here signals an end to this situ ation. Many of the difficulties inherent in working with relatively small amounts of material have been overcome, paving the way for application of a wider variety of experimental approaches to the zona pellucida by a larger community of investigators. Hopefully, this monograph will serve as a catalyst in this regard. As revealed in these pages, application of contemporary experi mental methodologies has had significant impact on both pure and applied research on the zona pellucida. For example, modem im munological approaches have been used to assess molecular fea tures of zona pellucida structure and function, as well as to evalu ate the zona pellucida as a potential contraceptive target antigen."

From 11 to 15 July 1977 about 60 physiologists, endo crinologists, ecologists and other biologists from 14 countries convened at the University Montpellier for a symposium on Environmental Endocrinology. This meet ing was organized as a Satellite Symposium of the 27th International Congress of Physiological Sciences, Paris, 18-23 July 1977. This volume is a record of the com munications presented at the symposium. The objectives of the program were to examine the role of the endocrine system in a wide spectrum of adjustments and adaptations to changes in environmental conditions by various spe cies of animals, including man, and to promote an ex change of ideas among investigators who have approached these functions from diverse aspects. The diversity of the information and ideas communicated is great. Of necessity, they represent only an extremely modest se lection of the many facets of endocrine function in the interaction of animals with their environments. Be yond the usefulness of the communications individually, we hope that they collectively demonstrate the substan tial heuristic value of the concept of environmental endocrinology as it was perceived by the participants. We acknowledge gratefully the kindness and sympathy of Professor Jaques ROUZAUD, President of the University of Montpellier II, for his generous extension of the hospitality of the University to the Symposium. We are most grateful to Mrs. Monique VIEU who effected so well the secretarial organization of the Sympos."

The Fifteenth Midwest Conference on Endocrinology and Metabolism, held at the University of Missouri-Columbia on October 11 and 12th, 1979, hosted the most prominent active researchers in the world on the subject of the hormone relaxin. Each speaker presented an in-depth coverage of his chosen topic and area of expertise. Some of the data presented in this book are findings which have not been pub lished in a scientific journal. The topic of this conference is especially timely in light of the fact that this is a first confer ence devoted specifically to the hormone relaxin. Progress on this hormone has been exceedingly rapid in recent years and many signif icant breakthroughs are documented in these pages. Lively discus sions following each presentation attest to the enthusiastic research effort being pursued at the present time concerning relaxin. Traditionally the Midwest Conferences on Endocrinology and Metabolism have emphasized breadth as well as depth of coverage. The present Conference has covered the many active areas of research in relaxin, including morphological aspects of the hormone's origin, chemical purification and chemical structure, bioassays, radioimmuno assays, receptors, mechanism of biochemical action and physiological responses to the hormone. Advances in relaxin were slow since its discovery by Dr. Frederick Hisaw, Sr. in 1926 until the availability of homogenous preparations some seven years ago. In the suceeding seven years, activity in the subject has accelerated remarkably."

This volume is the product of a symposium held on 14-16 February, 1985 in Ham- burg in honour of the 65th birthday of Prof. Hans-Joachim Schumann. Schumann was born on 28 December, 1919 in Stralsund. He studied medicine in Cologne, Greifswald and Rostock. The chair of pharmacology in Rostock was held at that time by Peter Holtz. It was he who first introduced Schumann to pharma- cology in 1944 and who was his Doktorvater (research supervisor). Mter the war, Schumann again worked with Holtz in Rostock and then in Frankfurt am Main. He received decisive stimuli during a research fellowship, in 1956, in Prof. J. H. Burn's department in Oxford, where he also worked with Prof. H. Blaschko. In 1964 he ac- cepted his present position as ordentlicher (full) Professor and Head of the Institute of Pharmacology and Toxicology of the then newly founded Medical Faculty of Es- sen. He has remained in Essen despite being offered the chair of pharmacology in G6ttingen in 1968. It is interesting to observe how in the main lines of his scientific work, which now spans 40 years, Schumann has followed the steps involved in autonomic neuro- transmission from transmitter release to transmitter-receptor interaction.